METABOLISM OF A NEW THIAZOLIDINEDIONE HYPOGLYCEMIC AGENT-CP-68,722 IN RAT - METABOLITE IDENTIFICATION BY GAS-CHROMATOGRAPHY MASS-SPECTROMETRY

1. After i.v. administration to rat of CP-68,722, a new thiazolidinedione antidiabetic drug, four metabolites were excreted in bile, as glucuronide conjugates. 2. Incubation of the drug with a rat liver microsomal preparation yielded the four in vivo metabolite aglycones and several additional in vitro metabolites. 3. Seven in vivo-generated metabolites were isolated by h.p.l.c. Each metabolite was converted to stable isotope labelled or non-labelled derivatives. Capillary g.l.c.-mass spectrometric analysis of the derivatives indicated that five metabolites result from hydroxylation and one from oxidation to the chromanone. The sites of metabolism were deduced from the electron ionization spectra. 4. Authentic standards for five metabolites were synthesized. Agreements of mass spectra and chromatographic retention times confirmed the five proposed structures. Two metabolites, detected only in vivo, await structure confirmation.